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Biomedical subjects

D A Lewis

Publications and source records attributed to D A Lewis.

At least 19 recordsLinked to original sources
PubMed2003

Noradrenaline-induced lipolysis in adipose tissue is suppressed at hibernation temperatures in ground squirrels.

Responsiveness of white adipose tissue (WAT) and brown adipose tissue (BAT) from hibernating and nonhibernating golden-mantled ground squirrels (Spermophilus lateralis) to the lipolytic action of the sympathetic neurotransmitter, noradrenaline, was tested in vitro at temperatures characteristic of deep torpor (5 degrees C) and euthermia (37 degrees C). Noradrenaline-stimulated lipolysis, as indicated by WAT glycerol release, of tissue from hibernating ground squirrels was six- to ten-fold greater at 37 degrees C than at 5 degrees C. Noradrenaline was ineffective in increasing lipolysis at 5 degrees C. Noradrenaline-stimulated lipolysis in BAT was similarly suppressed at 5 degrees C. Noradrenaline-stimulated lipolysis was little affected by temperature change below approximately 15 degrees C but strongly correlated with temperature above approximately 15 degrees C. Noradrenaline-induced lipolysis of WAT from nonhibernating and hibernating ground squirrels did not differ at an incubation temperature of 5 degrees C. We conclude that noradrenaline-stimulated WAT lipolytic activity is markedly suppressed at the low temperatures characteristic of deep torpor and that there is no 'hibernation-specific' adaptation of WAT to enhance its responsiveness to noradrenaline at low tissue temperatures. Temperature dependence of noradrenaline-stimulated lipolysis may in part account for the shift from lipid to carbohydrate metabolism during the earliest stage of arousal from deep torpor.

Adipose Tissue↗
PubMed2003

Chancroid: clinical manifestations, diagnosis, and management.

Chancroid is a sexually transmitted disease (STD) caused by the Gram negative bacterium Haemophilus ducreyi and is characterised by necrotising genital ulceration which may be accompanied by inguinal lymphadenitis or bubo formation. H ducreyi is a fastidious organism which is difficult to culture from genital ulcer material. DNA amplification techniques have shown improved diagnostic sensitivity but are only performed in a few laboratories. The management of chancroid in the tropics tends to be undertaken in the context of syndromic management of genital ulcer disease and treatment is usually with erythromycin. A number of single dose regimens are also available to treat H ducreyi infection. Genital ulceration as a syndrome has been associated with increased transmission of human immunodeficiency virus (HIV) infection in several cross sectional and longitudinal studies. Effective and early treatment of genital ulceration is therefore an important part of any strategy to control the spread of HIV infection in tropical countries.

Anti-Bacterial Agents↗
PubMed2003

Expression of the cytolethal distending toxin in a geographically diverse collection of Haemophilus ducreyi clinical isolates.

OBJECTIVE: To screen a collection of isolates of Haemophilus ducreyi for expression of the cytolethal distending toxin (CDT). METHODS: 45 clinical isolates of H ducreyi were screened for cytotoxic activity by examining the effect of culture supernatants on Hela cells. Expression was confirmed using immunoblotting with CDT specific monoclonal antibodies and the presence of the cdt genes determined by amplification of the cdt genes in a multiplex polymerase chain assay. RESULTS: Of the 45 clinical isolates, six isolates from differing geographical origins did not demonstrate cytotoxic activity. Expression of CDT was also not detected in these six isolates using immunoblotting and the genes cdtA, cdtB, and cdtC were not amplified using PCR. The remaining isolates demonstrated cytotoxic activity, expressed the CDT proteins, and the presence of the cdt genes was confirmed. CONCLUSIONS: CDT is considered a virulence factor of H ducreyi but was found to be absent in 13% of isolates from different geographical origins.

Bacterial Toxins↗
PubMed2002

Dopamine modulation of neuronal function in the monkey prefrontal cortex.

We developed a brain slice preparation that allowed us to apply whole-cell recordings to examine the electrophysiological properties of identified synapses, neurons, and local circuits in the dorsolateral prefrontal cortex (DLPFC) of macaque monkeys. In this article, we summarize the results from some of our recent and current in vitro studies in the DLPFC with special emphasis on the modulatory effects of dopamine (DA) receptor activation on pyramidal and nonpyramidal cell function in superficial layers in DLPFC areas 46 and 9.

Animals↗
PubMed2002

Dendritic morphology of callosal and ipsilateral projection neurons in monkey prefrontal cortex.

Subpopulations of cortical pyramidal neurons have been distinguished based on the projection target of their principal axons or by their dendritic morphology. In this study, we sought to test the hypothesis that pyramidal neurons in monkey prefrontal cortex that furnish callosal or ipsilateral projections have distinctive dendritic morphologies. Retrogradely-labeled, Fast Blue-containing callosal and ipsilateral neurons were intracellularly filled with Lucifer Yellow, immunoconverted, and reconstructed. Quantitative measurements of the size and complexity of the dendritic arbor, including total dendritic length, horizontal extent, number of branch points, maximum branch order, and number of segments, as well as spine density, were made. In general, callosal neurons had larger and more complex dendritic arbors for both apical and basilar dendritic trees than did ipsilateral neurons. The greatest difference was in total dendritic length; the apical and basilar trees of callosal neurons were 34 and 25% longer, respectively. In addition, spine density was also significantly greater on the apical and basilar dendrites of callosal neurons. These findings could not be explained by differences in somal size or completeness of dendritic filling between callosal and ipsilateral neurons. Our observations support the hypothesis that callosal and ipsilateral neurons differ on a number of measures of dendritic size and complexity. Furthermore, these findings imply that these two subpopulations of pyramidal cells differ in the number and perhaps types of excitatory inputs that they receive. Finally, differences in the dendritic morphology of callosal and ipsilateral neurons have implications for understanding the functional attributes of these two populations of cells, as well as for the characterization of pyramidal neurons in human disease states.

Amidines↗
PubMed2002

Localized decrease in serotonin transporter-immunoreactive axons in the prefrontal cortex of depressed subjects committing suicide.

A variety of postmortem brain studies and clinical investigations have provided evidence that reduced serotonin neurotransmission is associated with suicidal behavior and depression, and several serotonergic parameters have been found to be altered in the prefrontal cortex of suicide victims. However, the integrity of the serotonin innervation of the prefrontal cortex in mood disorders has not been directly investigated. The present study used immunocytochemical methods and an antibody against the serotonin transporter to examine the relative density of serotonin axons in the dorsolateral prefrontal cortex of suicide victims with a diagnosis of major depression. The mean total length of serotonin transporter-immunoreactive axons per unit area was unchanged in layers 2 and 4 of area 46 in the depressed suicide subjects compared to controls, but was significantly (P < 0.01) decreased by 24% in layer 6 in the depressed suicide group. The total length of serotonin transporter-positive axons in layer 6 was reduced in eight of the 12 depressed suicide subjects compared to their matched control subjects. These findings reveal that depressed subjects who have committed suicide exhibit a lamina-specific reduction in a marker of serotonin axons in the dorsolateral prefrontal cortex that may reflect an alteration in cortical serotonin neurotransmission.

Adult↗
PubMed2001

Myocardial performance and baroreceptor reflexes in preterm neonates: an echocardiographic evaluation using the tilt-table test.

The hemodynamic consequence of head-up position in preterm infants is not known, so we used the tilt-table test to assess changes in myocardial performance and baroreceptor reflexes. Twenty-five preterm infants with gestational age (GA) (mean +/- SD) 31 +/- 2.9 weeks (range 25-35.5 weeks), birth weight of 1612 +/- 642 g (range 520-3260 g) were studied in supine, 30 degrees, and 60 degrees head-up positions. GA had a significant effect on heart rate (HR) (p = 0.007), systolic blood pressure (SBP) (p = 0.03), left ventricular (LV) cavity dimensions (p = 0.001), cardiac output (CO) (p = 0.001), LV ejection time (LVETc) (p = 0.05), and end systolic wall stress (ESWS) (p = 0.003). An inverse relationship was seen between velocity of circumferential fiber shortening (VcFs) and ESWS (slope b = -0.019 +/- 0.008, p = 0.003). Results of tilt tests showed that at supine, 30 degrees, and 60 degrees, respectively, HR was 162 +/- 10.5, 162 +/- 9, and 164 +/-12 (p = NS); SBP (mmHg) was 73 +/- 11, 72.5 +/- 9.5, and 78 +/- 10 (p = NS); CO (L/kg/min) was 0.4 +/- 0.16, 0.4 +/- 0.15, and 0.43 +/- 0.16 (p = NS); ESWS (g/cm2) was 38.7 +/- 8.3, 40.9 +/- 9.9, and 43.4 +/- 10.7 (p = NS); and VcFs (circ/sec) was 1.35 +/- 0.3, 1.28 +/- 0.4, and 1.26 +/- 0.2 (p = NS). LV filling pattern as seen by early/late atrial Doppler flow velocity ratio did not change with tilt (p = NS). Myocardial performance improved with increasing GA. No significant differences in myocardial performance were found between baseline and head-up tilt positions.

Analysis of Variance↗
PubMed2001

Investigation of the interaction among the components of the cytolethal distending toxin of Haemophilus ducreyi.

The cytolethal distending toxin (CDT) of Haemophilus ducreyi is encoded by the cdtABC genes, but the composition of active CDT is not known. Both immunoaffinity and metal affinity chromatographic methods were used to purify H. ducreyi CDT from recombinant Escherichia coli strains bearing wild-type or mutated H. ducreyi cdtABC genes. Both affinity-purified preparations contained CdtA, CdtB, and CdtC proteins. These purification efforts also revealed that the formation of a noncovalent CdtB-CdtC complex and production of a fully active CDT complex required the presence of a functional CdtA protein. When purified recombinant CdtB and CdtC proteins were mixed, only very slight CDT activity was detected. In contrast, when a bacterial cell extract containing CdtA was mixed with purified preparations of both CdtB and CdtC, full CDT activity was reconstituted in vitro. These results indicate that CdtA is essential for normal H. ducreyi CDT activity and that CdtA likely modifies or alters either CdtB or CdtC or both to form the active CDT complex.

Bacterial Toxins↗
PubMed2001

Dopamine transporter immunoreactivity in monkey cerebral cortex: regional, laminar, and ultrastructural localization.

Dopamine (DA) influences a number of cognitive and motor functions that are mediated by the primate cerebral cortex, and the DA membrane transporter (DAT) is known to be a critical regulator of DA neurotransmission in subcortical structures in rodents. To gain insight into the possible functional role of cortical DAT, we compared the regional, laminar, and ultrastructural distribution of DAT immunoreactivity to that of tyrosine hydroxylase (TH), the rate-limiting enzyme in DA synthesis, in the cerebral cortex of macaque monkeys. DAT-immunoreactive (DAT-IR) axons were present throughout the cortical mantle, with substantial differences in density and laminar distribution across cytoarchitectonic areas. In particular, high densities of DAT-IR axons were present in certain regions (e.g., posterior parietal cortex, dentate gyrus) not previously thought to receive a substantial DA input. The laminar distribution of DAT-IR axons ranged from a restricted localization of labeled axons to layer 1 in lightly innervated regions to the presence of axons in all six cortical layers, with a particularly dense plexus in deep layer 3, in highly innervated regions. These regional and laminar patterns paralleled those of TH-IR axons, but several differences in fiber morphology and ultrastructural localization of DAT were observed. For example, in contrast to TH, DAT immunoreactivity in the cortex was localized predominantly to small-diameter profiles, whereas, in the dorsolateral caudate nucleus, DAT and TH immunoreactivities were present in both large-diameter and small-diameter profiles, which may represent varicose and intervaricose axon segments, respectively. Overall, the distribution of DAT-IR axons confirms and extends the results of previous reports, using other markers of DA axons, that the DA innervation of the primate cerebral cortex is global but specialized on both a regional basis and a laminar basis. In particular, these observations reveal an anatomical substrate for a direct and potent influence of DA over neuronal activity in posterior parietal cortex and in certain regions of the temporal lobe. However, due to its predominant distribution to small-diameter profiles, immunoreactivity for DAT may not be an appropriate ultrastructural marker for larger DA varicosities in the primate cortex. Moreover, this distribution of DAT suggests that cortical DA fibers may permit greater neurotransmitter diffusion than subcortical DA axons.

Animals↗
PubMed2001

Synaptic targets of the intrinsic axon collaterals of supragranular pyramidal neurons in monkey prefrontal cortex.

The principal axons of supragranular pyramidal neurons in the cerebral cortex travel through the white matter and terminate in other cortical areas, whereas their intrinsic axon collaterals course through the gray matter and form both local and long-distance connections within a cortical region. In the monkey prefrontal cortex (PFC), horizontally oriented, intrinsic axon collaterals from supragranular pyramidal neurons form a series of stripe-like clusters of axon terminals (Levitt et al. [1993] J Comp Neurol 338:360-376; Pucak et al. [1996] J Comp Neurol 376:614-630). The present study examined the synaptic targets of the intrinsic axon collaterals arising from supragranular pyramidal neurons within the same stripe (local projections). Approximately 50% of the within-stripe axon terminals in monkey PFC area 9 targeted dendritic spines. In contrast, for both the intrinsic axon collaterals that travel between stripes (long-range projections), and the axon terminals that project to other PFC areas (associational projections), over 92% of the postsynaptic structures were dendritic spines (Melchitzky et al. [1998] J Comp Neurol 390:211-224). The other 50% of the within-stripe terminals synapsed with dendritic shafts. Dual-labeling studies confirmed that these within-stripe terminals contacted gamma-aminobutyric acid-immunoreactive dendritic shafts, including the subpopulation that contains the calcium-binding protein parvalbumin. The functional significance of the differences in synaptic targets between local and long-range intrinsic axon collaterals was supported by whole-cell, patch clamp recordings in an in vitro slice preparation of monkey PFC. Specifically, the small amplitude responses observed in layer 3 pyramidal neurons during long-range, low-intensity stimulation were exclusively excitatory, whereas local stimulation also evoked di/polysynaptic inhibitory responses. These anatomic and electrophysiological findings suggest that intrinsic connections of the PFC differ from other cortical regions and that within the PFC, feedback (within-stripe) inhibition plays a greater role in regulating the activity of supragranular pyramidal neurons than does feedforward inhibition either between stripes or across regions.

Animals↗
PubMed2001

Alterations of striatal dopamine receptor binding in Alzheimer disease are associated with Lewy body pathology and antemortem psychosis.

BACKGROUND: Lewy bodies (LB) are present in at least 20% to 30% of persons with Alzheimer disease (AD) and contribute to the risk of psychosis and to excess cognitive burden. OBJECTIVE: To determine whether altered striatal dopamine receptor binding is associated with LB and psychosis in AD. DESIGN: Postmortem case control. SETTING: Alzheimer's Disease Research Center at the University of Pittsburgh (Pa). PARTICIPANTS: Consecutive cases from the Alzheimer's Disease Research Center brain bank, neuroleptic free for at least 1 month prior to death, with neuropathologic diagnoses of AD with LB (AD + LB, n = 14), AD without LB (AD, n = 13), or normal brains (n = 8). MAIN OUTCOME MEASURES: Dopamine D1, D2, and D3 receptor densities, and affinities as determined by selective saturation binding studies in striatal tissue. RESULTS: Subjects with AD + LB, compared with those with AD, demonstrated increased D1 receptor density and decreased D2 and D3 receptor density. D3 receptor density was selectively increased, however, in AD subjects with a history of psychosis, independent of the presence or absence of LB. The effect of neuroleptic treatment on D3 binding was further examined in an additional group of subjects who had received neuroleptics near the time of death. Neuroleptic treatment reduced D3 affinity with no effect on D3 density. CONCLUSIONS: Alzheimer disease with LB is associated with selective alterations in dopamine receptor density, which may contribute to the distinct clinical profile of this group. The D3 receptor may be an important target of neuroleptic treatment of psychosis in AD.

Aged↗
PubMed2001

Decreased somal size of deep layer 3 pyramidal neurons in the prefrontal cortex of subjects with schizophrenia.

BACKGROUND: Schizophrenia is associated with deficits in working memory, a cognitive function that depends on the connections of the prefrontal cortex (PFC) with the thalamus and other cortical regions. Pyramidal neurons in PFC deep layer 3 play a central role in both thalamocortical and corticocortical circuitry. Given that somal size tends to be associated with both the dendritic and axonal architecture of a neuron, abnormalities in these circuits in schizophrenia may be associated with a change in the somal size of deep layer 3 pyramidal neurons. METHODS: We used design-based stereology to estimate the somal volume of pyramidal neurons in deep layer 3 of PFC area 9 in 28 subjects with schizophrenia, each of whom was matched to 1 normal comparison subject for sex, age, and postmortem interval. RESULTS: The geometric mean of the somal volume estimates in the subjects with schizophrenia was significantly (P =.02) decreased by 9.2%. This decrease was associated with a shift in the distribution of somal volumes toward smaller sizes. Neither antipsychotic medication treatment history nor duration of illness was associated with somal size. CONCLUSIONS: These findings independently replicate previous reports of decreased somal size in the PFC in schizophrenia. The reduction in size of deep layer 3 pyramidal neurons is consistent with abnormalities in thalamocortical and corticocortical circuitry, suggesting that disruption of these circuits may contribute to cognitive abnormalities in schizophrenia.

Adult↗
PubMed2001

Analysis of complex brain disorders with gene expression microarrays: schizophrenia as a disease of the synapse.

The level of cellular and molecular complexity of the nervous system creates unique problems for the neuroscientist in the design and implementation of functional genomic studies. Microarray technologies can be powerful, with limitations, when applied to the analysis of human brain disorders. Recently, using cDNA microarrays, altered gene expression patterns between subjects with schizophrenia and controls were shown. Functional data mining led to two novel discoveries: a consistent decrease in the group of transcripts encoding proteins that regulate presynaptic function; and the most changed gene, which has never been previously associated with schizophrenia, regulator of G-protein signaling 4. From these and other findings, a hypothesis has been formulated to suggest that schizophrenia is a disease of the synapse. In the context of a neurodevelopmental model, it is proposed that impaired mechanics of synaptic transmission in specific neural circuits during childhood and adolescence ultimately results in altered synapse formation or pruning, or both, which manifest in the clinical onset of the disease.

Brain Chemistry↗
PubMed2001

Dopamine transporter-immunoreactive axons in the mediodorsal thalamic nucleus of the macaque monkey.

The reciprocal connections between the mediodorsal thalamic nucleus and the prefrontal cortex participate in a circuit that is essential to a number of higher cognitive processes. Projections from the dopamine-containing cells of the ventral mesencephalon to the prefrontal cortex are also critical for these cognitive abilities. It is unclear, however, whether dopamine axons innervate the mediodorsal thalamic nucleus in primates. In order to address this question, we examined the distribution of dopamine transporter-immunoreactive axons in the mediodorsal thalamic nucleus of macaque monkeys. Labeled axons were distributed quite heterogeneously in this nucleus, and did not strictly follow cytoarchitectonic subdivision boundaries. The ventral and lateral portions of the mediodorsal thalamic nucleus, which include parts of the parvicellular and multiform subdivisions, had the highest density of dopamine transporter-immunoreactive axons. In contrast, the dorsomedial portion, which included primarily the magnocellular subdivision, had the lowest density of labeled axons. In both lightly and densely innervated portions of the nucleus, small, dense clusters of dopamine transporter-immunoreactive axons were present. Axons immunoreactive for tyrosine hydroxylase were distributed in a pattern very similar to that of dopamine transporter-labeled axons. In contrast, noradrenergic axons, as revealed by dopamine beta-hydroxylase immunoreactivity, were present in higher density and were more evenly distributed throughout the mediodorsal thalamic nucleus. This dopamine innervation of the mediodorsal thalamic nucleus reveals another possible anatomical substrate through which dopamine may influence the cognitive functions mediated by thalamo-prefrontal circuitry.

Animals↗